技术领域technical field
本发明包括用于治疗指甲真菌感染的组合物。所述组合物用于指甲的局部治疗，并使得抗真菌物质能够渗透进入和穿过指甲。The present invention includes compositions for treating fungal nail infections. The composition is used in the topical treatment of the nails and enables the penetration of antifungal substances into and through the nails.
背景技术Background technique
指甲发生真菌感染（甲癣）随后出现指甲破坏的问题已经付诸了诸多努力，但目前手边没有临床上满意的解决方案。然而，有一个一般性的共识是：如果能够将足够量的有效的抗真菌化合物分布到整个指甲并进入甲床中，则该种感染会被治愈且对指甲的破坏会终止。The problem of fungal infection of the nails (onychomycosis) followed by nail destruction has been the subject of many efforts, but no clinically satisfactory solutions are currently at hand. However, there is a general consensus that if a sufficient amount of an effective antifungal compound can be distributed throughout the nail and into the nail bed, the infection will heal and damage to the nail will cease.
现有技术current technology
在现有技术中描述过几种提高抗真菌剂渗透的尝试。Several attempts to increase the penetration of antifungal agents have been described in the prior art.
美国专利7,820,720描述了一种适于局部递送特比萘芬的药物制剂，其包括：在水溶液中，i)含量为按重量计从大约0.5%到大约10%的特比萘芬或其药学上可接受的盐，ii)含量为按重量计从大约4%到大约7%的磷脂，以及iii)含量为从大约1%到大约4%的非离子表面活性剂。U.S. Patent 7,820,720 describes a pharmaceutical formulation suitable for topical delivery of terbinafine, comprising: in an aqueous solution, i) terbinafine or its pharmaceutical form in an amount of from about 0.5% to about 10% by weight; Acceptable salts are ii) phospholipids in amounts of from about 4% to about 7% by weight, and iii) nonionic surfactants in amounts of from about 1% to about 4%.
美国专利7,678,366描述了一种用于治疗指甲和/或周围组织的真菌感染的持续释放的治疗用甲油，其包括：a.抗真菌量的萘替芬或特比萘芬；b.角质层分离剂；c.至少大约3%的湿润剂，其中所述湿润剂为山梨糖醇、甘油或它们的混合物；d.含量为所述甲油溶液的0.5到少于大约5%的水；e.占非挥发性组分总重量的大约8%到大约35%的疏水性甲基丙酸烯聚合物；以及f.相当于所述组合物的总重量的大约60%到大约90%的量的挥发性溶剂，所述挥发性溶剂选自由醇、酮及它们的混合物组成的组。US Patent 7,678,366 describes a sustained release therapeutic nail polish for the treatment of fungal infections of the nail and/or surrounding tissue comprising: a. an antifungal amount of naftifine or terbinafine; b. cuticles A separating agent; c. at least about 3% of a wetting agent, wherein said wetting agent is sorbitol, glycerin, or a mixture thereof; d. water in an amount of 0.5 to less than about 5% of said nail polish solution; e . a hydrophobic methacrylic polymer comprising from about 8% to about 35% by weight of the total non-volatile components; and f. an amount corresponding to from about 60% to about 90% by weight of the composition A volatile solvent selected from the group consisting of alcohols, ketones, and mixtures thereof.
美国专利7,074,392公开了一种持续释放的治疗用甲油组合物，其包括：（a）抗真菌有效量的抗真菌剂；（b）足以增加并促进所述抗真菌剂渗透进所述指甲中的量的角质层分离剂；（c）多于3%（w/w）的湿润剂；（d）足以将指甲水化（hydrate）的量的水；（e）液态甲油组分，其包括聚合膜生成剂和挥发性溶剂，选择的所述生成剂在将所述组合物涂在指甲上并在所述挥发性溶剂蒸发后形成持续释放的薄膜。US Patent 7,074,392 discloses a sustained release therapeutic nail polish composition comprising: (a) an antifungal effective amount of an antifungal agent; (b) sufficient to increase and facilitate penetration of said antifungal agent into said nail (c) more than 3% (w/w) of a wetting agent; (d) water in an amount sufficient to hydrate the nail; (e) a liquid nail polish component, which Comprising a polymeric film former and a volatile solvent, said former is selected to form a sustained release film upon application of said composition to a nail and upon evaporation of said volatile solvent.
发明内容Contents of the invention
需要具有高渗透性的用于治疗甲癣的抗真菌组合物。There is a need for antifungal compositions with high permeability for the treatment of onychomycosis.
此外，需要具有高浓度的活性抗真菌化合物的制剂。Furthermore, there is a need for formulations with high concentrations of active antifungal compounds.
此外，通常需要抗真菌化合物可溶于制剂中，即，其不沉淀。Furthermore, it is generally required that the antifungal compound is soluble in the formulation, ie that it does not precipitate.
本发明的一个目的是落实至少一些上面所列的问题。因此，本发明的第一主要方面提供了一种用于治疗指甲的真菌感染的药物组合物，其包括含量为多于5%的抗真菌丙烯胺、有机酸或其酯、二醇和多价螯合剂（sequestering agent），其中所述药物组合物基本上不含水。It is an aim of the present invention to address at least some of the problems listed above. Accordingly, a first main aspect of the present invention provides a pharmaceutical composition for the treatment of fungal infections of the nails comprising an antifungal allylamine, an organic acid or an ester thereof, a glycol and a sequestrant in an amount greater than 5%. A sequestering agent, wherein the pharmaceutical composition is substantially free of water.
具体实施方式Detailed ways
在下文中给出了本发明的详细描述。A detailed description of the present invention is given below.
如本文中所使用，除非另外规定，组分以百分比的含量指的是重量百分数，且基于所述组合物的总重量。As used herein, unless otherwise specified, the amounts of components in percentages refer to percentages by weight and are based on the total weight of the composition.
如果适用的话，术语“大约”用于表示规定值的±10%的偏差。例如，“大约20%”表示从18%到22%的值。Where applicable, the term "about" is used to indicate a deviation of ±10% from the stated value. For example, "about 20%" indicates a value from 18% to 22%.
所述组合物基本上不含水。没有水被加入所述制剂中。然而，由于某些组分可能含有少量的水，因此组合物中仍有可能有痕量的水。痕量的水低于5%，更优选低于3%，更优选为2%，更优选低于1%，更优选低于0.5%以及最优选低于0.3%。The composition is substantially free of water. No water was added to the formulation. However, since certain components may contain small amounts of water, there may still be traces of water in the composition. Trace amounts of water are less than 5%, more preferably less than 3%, more preferably less than 2%, more preferably less than 1%, more preferably less than 0.5% and most preferably less than 0.3%.
如果向所述制剂中加入水，所述抗真菌化合物会沉淀从而失去活性，这在该系统中是不希望的，因为在施用后可用于治疗的特比萘芬的量减少了。If water is added to the formulation, the antifungal compound will precipitate and lose its activity, which is undesirable in this system because the amount of terbinafine available for treatment after application is reduced.
本发明的另一优势为其含有高浓度，多于5%的抗真菌物质。这增加了所述抗真菌组合物的效能。Another advantage of the present invention is that it contains a high concentration, more than 5%, of antifungal substances. This increases the efficacy of the antifungal composition.
所述抗真菌丙烯胺溶于组合物中。因此，该制剂以溶液（即：单相系统）存在。The antifungal allylamine is dissolved in the composition. Therefore, the formulation exists as a solution (ie: a single-phase system).
丙烯胺抗真菌剂，特别是特比萘芬和萘替芬，是本发明优选的抗真菌剂。这些物质通过阻断角鲨烯环氧酶，一种在真菌麦角固醇生物合成中的关键酶而抑制真菌的生长。合适的丙烯胺抗真菌剂的实例包括选自由阿莫罗芬、布替萘芬、特比萘芬和萘替芬及它们的混合物组成的组的丙烯胺抗真菌剂。这些是丙烯胺抗真菌剂的非限制性的实例。特比萘芬是本发明最优选的丙烯胺抗真菌剂。Allylamine antifungal agents, especially terbinafine and naftifine, are preferred antifungal agents of the invention. These substances inhibit fungal growth by blocking squalene epoxidase, a key enzyme in fungal ergosterol biosynthesis. Examples of suitable allylamine antifungal agents include allylamine antifungal agents selected from the group consisting of amorolfine, butenafine, terbinafine and naftifine, and mixtures thereof. These are non-limiting examples of allylamine antifungal agents. Terbinafine is the most preferred allylamine antifungal agent of the present invention.
丙烯胺在制剂中的含量为从1%到12%。丙烯胺的量优选为大约10%。12%是丙烯胺在本发明的制剂中溶解度的接近极限值。丙烯胺的量优选为从5%到12%，更优选为从8%到12%，且最优选为从10.5%到12%。然而，丙烯胺的溶解度可根据温度以及所包括的化合物的性质而变化。可选地，当丙烯胺在所述组合物中的溶解度的上限为11.5%时，丙烯胺的优选量为从5%到11.5%，更优选为从8%到11.5%，且最优选为从10.5%到11.5%。The content of allylamine in the formulation is from 1% to 12%. The amount of allylamine is preferably about 10%. 12% is close to the limiting value for the solubility of allylamine in the formulations of the invention. The amount of allylamine is preferably from 5% to 12%, more preferably from 8% to 12%, and most preferably from 10.5% to 12%. However, the solubility of allylamine can vary depending on the temperature as well as the nature of the compounds involved. Alternatively, when the upper limit of the solubility of allylamine in the composition is 11.5%, the preferred amount of allylamine is from 5% to 11.5%, more preferably from 8% to 11.5%, and most preferably from 10.5% to 11.5%.
本发明的组合物包括有机酸或其酯以及醇。这导致所述丙烯胺抗真菌化合物的出乎意料的高溶解度以及递送进入并穿过角化组织。The compositions of the present invention include organic acids or esters thereof and alcohols. This results in unexpectedly high solubility and delivery of the allylamine antifungal compound into and through keratinized tissue.
有机酸为C1-8羧酸。C1-8羧酸的实例包括具有1、2、3、4、5、6、7或8个碳原子的任意的一种或多种饱和或不饱和的、直链或支链的脂肪族单-、二-及多聚羧酸，具有1、2、3、4、5、6、7或8个碳原子的芳脂族（araliphatic）或芳香二羧酸、氧基及羟基羧酸（例如α-羟基酸）。合适的有机酸组分的实例包括蚁酸、乙酸、丙酸、丁酸、戊酸、己酸、山梨酸、草酸、柠檬酸、丙二酸、富马酸、琥珀酸、戊二酸、己二酸(apidic acid)、庚二酸、草乙酸、苹果酸、酒石酸、丙醇二酸、羟基丁酸、羟基丙酸和丙酮酸中的一种或多种。有机酸优选为乳酸。Organic acid is C1-8 carboxylic acid. Examples of C1-8 carboxylic acids include any one or more saturated or unsaturated, linear or branched aliphatic compounds having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Mono-, di- and polycarboxylic acids, araliphatic or aromatic dicarboxylic acids, oxy- and hydroxycarboxylic acids ( such as alpha-hydroxy acids). Examples of suitable organic acid components include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, sorbic acid, oxalic acid, citric acid, malonic acid, fumaric acid, succinic acid, glutaric acid, hexanoic acid, One or more of apidic acid, pimelic acid, oxalic acid, malic acid, tartaric acid, tartronic acid, hydroxybutyric acid, hydroxypropionic acid and pyruvic acid. The organic acid is preferably lactic acid.
作为所述有机酸的一种替换，所述组合物可包括合适有机酸的C1-4烷基酯，或合适的有机酸与所述有机酸的酯的混合物。优选的酯为乳酸的酯。合适的酯的非限制性实例为乳酸甲酯、乳酸乙酯、乳酸丁酯和乳酸丙酯。As an alternative to the organic acid, the composition may include aC1-4 alkyl ester of a suitable organic acid, or a mixture of a suitable organic acid and an ester of the organic acid. Preferred esters are esters of lactic acid. Non-limiting examples of suitable esters are methyl lactate, ethyl lactate, butyl lactate and propyl lactate.
所述组合物中存在的有机酸或其酯或其混合物的量为从1%到30%，更优选为从5%到25%，更优选为从7%到22%，以及最优选为从8%到20%。The organic acid or its ester or mixture thereof is present in the composition in an amount of from 1% to 30%, more preferably from 5% to 25%, more preferably from 7% to 22%, and most preferably from 8% to 20%.
合适的二醇为丙二醇、丁二醇、戊二醇和己二醇，其中丙二醇和丁二醇是特别合适的。所提到的二醇的混合物也是合适的。Suitable diols are propylene glycol, butanediol, pentanediol and hexylene glycol, with propylene glycol and butanediol being particularly suitable. Mixtures of the diols mentioned are also suitable.
所述二醇或其混合物应优选以多于50%，更优选为从50%到95%，更优选为从50%到90%，更优选为从60%到90%以及最优选为大约从67.5%到大约84%的量使用。The diol or mixture thereof should preferably be present in an amount of more than 50%, more preferably from 50% to 95%, more preferably from 50% to 90%, more preferably from 60% to 90% and most preferably from about 67.5% to about 84% is used.
所述组合物包括多价螯合剂。加入多价螯合剂出人意料地提高了丙烯胺向指甲中的递送。合适的多价螯合剂的非限制性实例包括氨基乙酸、膦酸酯、膦酸及这些的混合物中的一种或多种。多价螯合剂可以为可与金属例如碱金属或碱土金属形成络合物的金属络合剂。优选的多价螯合剂为乙二胺四乙酸（EDTA）。合适量的多价螯合剂的实例包括从0.01%到5%，优选为从0.02%到3%，更优选为从0.03%到1%。The composition includes a sequestrant. The addition of a sequestering agent unexpectedly enhanced the delivery of allylamine into the nail. Non-limiting examples of suitable sequestrants include one or more of glycine, phosphonates, phosphonic acids, and mixtures of these. The sequestering agent may be a metal complexing agent that can form complexes with metals, such as alkali metals or alkaline earth metals. A preferred sequestering agent is ethylenediaminetetraacetic acid (EDTA). Examples of suitable amounts of sequestrants include from 0.01% to 5%, preferably from 0.02% to 3%, more preferably from 0.03% to 1%.
所述组合物优选包括从大约67.5%到大约84%的丙二醇，从8%到20%的乳酸，从0.03%到0.1%的EDTA和从8%到12%的特比萘芬。The composition preferably comprises from about 67.5% to about 84% propylene glycol, from 8% to 20% lactic acid, from 0.03% to 0.1% EDTA and from 8% to 12% terbinafine.
本发明优选的组合物也为在实施例部分中的实施例A、B、C、D、E、F、G、H、I、J、K、L、ISM09024、ISM09017、ISM09018和ISM09016的那些。Preferred compositions of the invention are also those of Examples A, B, C, D, E, F, G, H, I, J, K, L, ISM09024, ISM09017, ISM09018 and ISM09016 in the Examples section.
所述制剂可包括对制剂的作用及稳定性有益的其他组分。这样的成分的实例为尿素、含巯基的氨基酸及其他角蛋白降解剂。角蛋白降解剂的实例为半胱氨酸、乙酰半胱氨酸和巯基酸。The formulation may include other components that are beneficial to the action and stability of the formulation. Examples of such ingredients are urea, thiol-containing amino acids and other keratin degrading agents. Examples of keratin degrading agents are cysteine, acetylcysteine and mercapto acids.
也可加入改善所述制剂质地（texture）的组分例如聚合物及其他粘性增强剂，以及掩蔽剂和着色剂。此外，可以向所述制剂中加入具有缓冲能力及抗微生物性质的标准皮肤病学组分，条件是这些组分可溶于且共存于所述新的组合物。Components that improve the texture of the formulation, such as polymers and other viscosity enhancing agents, as well as masking and coloring agents, may also be added. In addition, standard dermatological components having buffering capacity and antimicrobial properties can be added to the formulation, provided that these components are soluble and co-present in the novel composition.
本发明的制剂用于施用到指甲上。所述制剂要被用于治疗指甲的真菌感染。然而，也可将本发明的制剂用于治疗其他类型的角化组织（例如茧）的真菌感染。The formulations of the invention are intended for application to nails. The formulation is intended to be used for the treatment of fungal infections of the nails. However, the formulations of the invention may also be used to treat fungal infections of other types of keratinized tissue, such as calluses.
在本发明的第二主要方面，提供了本发明的组合物用于治疗指甲的真菌感染的用途。In a second main aspect of the invention there is provided the use of a composition of the invention for the treatment of fungal infections of the nails.
在本发明的第三主要方面，提供了治疗指甲真菌感染的方法，其中向患者施用本发明的组合物。In a third main aspect of the present invention there is provided a method of treating fungal nail infections wherein a composition of the present invention is administered to a patient.
实施例Example
为评价本发明制剂的效果，我们采用Franz细胞的体外渗透法。我们将蹄膜用作指甲的替代品。在这种类型的实验中，蹄是人类指甲的一种可接受的模型（Mertin,D.Lippold,B.C.“In-vitro permeability of the human nail and of a keratinmembrane from bovine hooves:prediction of the penetration rate ofantimycotics through the nail plate and their efficacy（人类指甲和牛蹄的角蛋白膜的体外渗透性：预测抗真菌剂通过指甲板的渗透速率及它们的效力）”J PharmPharmacol,1997,49(9),866-72）（cit.Mertin和Lippold1997）。To evaluate the effect of the formulations of the invention, we used the in vitro permeation method of Franz cells. We use hoof membranes as a substitute for nails. The hoof is an acceptable model for the human nail in this type of experiment (Mertin, D. Lippold, B.C. "In-vitro permeability of the human nail and of a keratin membrane from bovine hooves: prediction of the penetration rate of antimycotics through the nail plate and their efficacy (in vitro permeability of keratin membranes of human nails and bovine hooves: prediction of penetration rates of antifungal agents through the nail plate and their efficacy)" J PharmPharmacol, 1997, 49(9), 866-72 ) (cit. Mertin and Lippold 1997).
按照Mertin和Lippold,1997中的描述进行体外药物渗透实验。进行如下实验。将pH3.7的0.1M柠檬酸盐缓冲液用作Franz细胞中的受体溶液。在实验前用氦气将所述受体溶液脱气10分钟。仅使用牛蹄底部的蹄膜。使用的特比萘芬为特比萘芬盐酸盐形式。In vitro drug permeation experiments were performed as described in Mertin and Lippold, 1997. Carry out the following experiments. 0.1 M citrate buffer at pH 3.7 was used as the acceptor solution in Franz cells. The receptor solution was degassed with helium for 10 minutes prior to the experiment. Only use the hoof membrane from the bottom of the hoof. The terbinafine used was in the form of terbinafine hydrochloride.
在水化15分钟后，将蹄膜装在扩散细胞中。在进行扩散6小时后取样。所有的体外渗透实验按一式三份进行。After 15 minutes of hydration, the hoof membranes were packed in spreading cells. Samples were taken 6 hours after the diffusion was performed. All in vitro permeation experiments were performed in triplicate.
将通过量（flux）归一化至1%特比萘芬的通过量。因此，此处将通过量描述成μg特比萘芬/%tbf*h*cm2，并将渗透实验的结果按照如下等式进行计算：The flux was normalized to that of 1% terbinafine. Therefore, the throughput is described here as μg terbinafine/%tbf*h*cm2 , and the results of the permeation experiments are calculated according to the following equation:
归一化的通过量=Δm/(Δt*A*%tbf)Normalized throughput=Δm/(Δt*A*%tbf)
其中in
Δm=在受体液体中特比萘芬的增加的质量，以μg计Δm = added mass of terbinafine in receptor fluid, in μg
Δt=两次观察之间的时间，以小时计Δt = time between two observations in hours
A=膜表面积，以cm2计A = Membrane surface area incm2
%tbf=组合物中特比萘芬的重量百分率%tbf=the weight percent of terbinafine in the composition
实施例1在不同水平乳酸的制剂中特比萘芬通过量Example 1 Throughput of terbinafine in formulations with different levels of lactic acid
在该实验中说明了制剂中乳酸的作用。将乳酸从0%增加到20%产生的通过量增高了两倍（表1中的组合物C比组合物E）。The effect of lactic acid in the formulation is illustrated in this experiment. Increasing lactic acid from 0% to 20% produced a two-fold increase in throughput (Composition C vs. Composition E in Table 1).
表1.Table 1.
实施例2Example 2
在该实施例中，丙二醇部分地被其他二醇替换。从渗透的角度看，戊二醇似乎具有与比己二醇表现更好的丙二醇对渗透相同的作用。In this example, propylene glycol was partially replaced by other diols. From an osmotic standpoint, pentylene glycol appears to have the same effect on osmosis as propylene glycol, which performs better than hexylene glycol.
表2.Table 2.
实施例3Example 3
研究了尿素的量与特比萘芬渗透之间的关系。向制剂中引入尿素对特比萘芬的渗透没有影响。The relationship between the amount of urea and the penetration of terbinafine was studied. The introduction of urea into the formulation had no effect on the penetration of terbinafine.
表3table 3
实施例4含尿素和乙酰半胱氨酸的组合的组合物Example 4 Compositions Comprising Combinations of Urea and Acetylcysteine
表4.Table 4.
在该实验中制备了四种组合物。在表4中列出了这些组合物，并通过将所述成分溶解在丙二醇中进行制备。Four compositions were prepared in this experiment. These compositions are listed in Table 4 and were prepared by dissolving the ingredients in propylene glycol.
在表4中，当在制剂中加入乙酰半胱氨酸时，通过量增加了40%。增加乙酰半胱氨酸的浓度不会增加通过量。然而，维持尿素与乙酰半胱氨酸1:1的比例并将两者的浓度从10%增加到15%使得通过量增加了40%。In Table 4, the throughput increased by 40% when acetylcysteine was added to the formulation. Increasing the concentration of acetylcysteine did not increase throughput. However, maintaining a 1:1 ratio of urea to acetylcysteine and increasing the concentration of both from 10% to 15% resulted in a 40% increase in throughput.
实施例5EDTA的作用The effect of embodiment 5EDTA
为了稳定本发明的组合物中的组分，向制剂中加入EDTA。在体外实验中，我们惊讶地发现，特比萘芬的通过量从一个已经很高的水平增加了30%。在表5中给出了数据。To stabilize the components in the compositions of the present invention, EDTA is added to the formulation. In in vitro experiments, we were surprised to see a 30% increase in terbinafine throughput from an already high level. The data are given in Table 5.
表5.table 5.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811087157.7ACN109453150A (en) | 2011-02-11 | 2012-02-10 | New antifungal composition |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE1150107-9 | 2011-02-11 | ||
| SE1150107 | 2011-02-11 | ||
| PCT/EP2012/052327WO2012107565A1 (en) | 2011-02-11 | 2012-02-10 | Novel antifungal composition |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811087157.7ADivisionCN109453150A (en) | 2011-02-11 | 2012-02-10 | New antifungal composition |
| Publication Number | Publication Date |
|---|---|
| CN103384518A CN103384518A (en) | 2013-11-06 |
| CN103384518Btrue CN103384518B (en) | 2018-10-26 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811087157.7APendingCN109453150A (en) | 2011-02-11 | 2012-02-10 | New antifungal composition |
| CN201280007874.9AActiveCN103384518B (en) | 2011-02-11 | 2012-02-10 | new antifungal composition |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811087157.7APendingCN109453150A (en) | 2011-02-11 | 2012-02-10 | New antifungal composition |
| Country | Link |
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| US (3) | US8952070B2 (en) |
| EP (1) | EP2672962B1 (en) |
| JP (1) | JP5883886B2 (en) |
| KR (1) | KR101647545B1 (en) |
| CN (2) | CN109453150A (en) |
| AU (1) | AU2012215383B2 (en) |
| BR (1) | BR112013020456B1 (en) |
| CA (1) | CA2826741C (en) |
| CY (1) | CY1116275T1 (en) |
| DK (1) | DK2672962T3 (en) |
| ES (1) | ES2535827T3 (en) |
| HR (1) | HRP20150507T1 (en) |
| IL (1) | IL227765A (en) |
| ME (1) | ME02152B (en) |
| MX (1) | MX335945B (en) |
| PL (1) | PL2672962T3 (en) |
| PT (1) | PT2672962E (en) |
| RS (1) | RS53982B1 (en) |
| RU (1) | RU2587064C2 (en) |
| SG (1) | SG192615A1 (en) |
| SI (1) | SI2672962T1 (en) |
| SM (1) | SMT201500154B (en) |
| WO (1) | WO2012107565A1 (en) |
| ZA (1) | ZA201305891B (en) |
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